Studies of diaphragm fatigue and dysfunction

Diaphragm fatigue and dysfunction are important components of acute and chronic respiratory pump failure. We lack knowledge about the nature of diaphragm fatigue and the pathophysiological and morphological changes that occur in the diaphragm after prolonged mechanical ventilation. This thesis studied two aspects of diaphragm function. Diaphragm contractility and oxidative metabolism were studied during inspiratory resistive loaded breathing (IRB) and hypoxia, and diaphragm contractility, activation and morphology were examined during prolonged mechanical ventilation. Additionally, ultrasonography was evaluated as a quantitative measure of diaphragm function.

Methods: Anesthetized piglets ages 4-6 weeks (studies I, II, III) or 2-4 months (studies IV, V) were studied. Diaphragm contractility was evaluated in all studies by measurement of transdiaphragmatic pressure, Pdi achieved by supramaximal phrenic nerve stimulation with transvenous stimulation electrodes. Intracellular high energy phosphates (ATP, phosphocreatine) were measured b y 31 phosphorus nuclear magnetic spectroscopy (NMS) following diaphragm fatigue induced by repetitive phrenic nerve stimulation and IRB (study I), as well as IRB and hypoxia (study II). Ultrasonography measurements of the posterior diaphragm were obtained in die transverse and lateral sagital planes, using 2D and m-modes, and were tested for agreement with measures of contractility before and after evoked diaphragm fatigue (study III). Combined diaphragm EMG, phrenic nerve- diaphragm electroneurogram and Pdi were obtained daily in studies of prolonged, controlled mechanical ventilation and evaluated along with repeated measures of dynamic lung compliance and airway resistance (study IV). Morphology, fiber type proportions and size were studied from diaphragm biopsies obtained from study animals and compared to controls (study V).

Results: Spontaneous inspiratory resistive breathing led to respiratory failure (acidosis and hypercarbia) but preserved peripheral diaphragm contractility and oxidative metabolism. The addition of hypoxemia to ERB did result however, in decreased Pdi and signs of inadequate oxidative metabolism (rise in ratio of inorganic phosphate to phosphocreatine). Diaphragm fatigue induced by repetitive phrenic nerve stimulation was associated with a change in ultrasound m-mode measurement of mean inspiratory velocity of the right posterior hemidiaphragm. Prolonged mechanical ventilation and diapluagm inactivity over 5 days resulted in decreased Pdi over frequencies from 20 to 100 Hz and activation as measured by compound muscle action potential amplitude. Nerve conduction and neuromuscular transmission remained in tact. Morphologic signs of muscle adaptation or injury included areas of regeneration, micro-vacuolization and poor histologic staining for m-ATPase, which may be associated with loss of myosin.

Conclusions: Acute respiratory failure in anesthetized piglets during spontaneous inspiratory resistive breathing is not caused by diaphragm fatigue due to decreased contractility or inadequate diaphragm oxidative metabolism. Ile addition of severe hypoxemia to inspiratory resistive breathing results, however, in inadequate oxidative metabolism and decreased contractility which may contribute to the respiratory failure seen. Utrasonography can be used to quantify diaphragm function and identify diaphragm fatigue in this setting. Prolonged controlled mechanical ventilation and diaphragm inactivity results in decreased diaphragm activation and contractility. Changes in neurophysiologic measures and diaphragm muscle fiber morphology indicate that the contractile dysfunction seen occurs at the level of diaphragm muscle rather than in nerve conduction or neuromuscular transmission.

List of scientific papers

I. Radell PJ, Eleff SM, Traystman RJ, Nichols DG (1997). "In vivo diaphragm metabolism: comparison of paced and inspiratory resistive loaded breathing in piglets. " Crit Care Med 25(2): 339-45
https://pubmed.ncbi.nlm.nih.gov/9034274

II. Radell PJ, Eleff SM, Nichols DG (2000). "Effects of loaded breathing and hypoxia on diaphragm metabolism as measured by (31)P-NMR spectroscopy. " J Appl Physiol 88(3): 933-8
https://pubmed.ncbi.nlm.nih.gov/10710388

III. Kocis KC, Radell PJ, Sternberger WI, Benson JE, Traystman RJ, Nichols DG (1997). "Ultrasound evaluation of piglet diaphragm function before and after fatigue. " J Appl Physiol 83(5): 1654-9
https://pubmed.ncbi.nlm.nih.gov/9375335

IV. Radell PJ, Remahl S, Nichols DG, Eriksson LI (2001). "Effects of prolonged mechanical ventilation and inactivity on piglet diaphragm function." (Submitted)

V. Radell PJ, Eriksson LI, Ansved T (2001). "Diaphragm morphology following prolonged mechanical ventilation and inactivity." (Manuscript)